Treatment Study DRAXXIN vs. Nuflor July 2005 Comparative efficacy of DRAXXIN or Nuflor for the treatment of undifferentiated bovine respiratory disease in feeder cattle Pfizer Animal Health, New York, NY Key Points DRAXXIN (tulathromycin) Injectable Solution administered as a single subcutaneous (SC) injection was safe and effective for the treatment of undifferentiated bovine respiratory disease (BRD). DRAXXIN was significantly more effective, in 2 studies with feeder cattle, than was Nuflor (florfenicol) Injectable Solution. First-treatment success, in both studies, for days 3 to 28 was significantly higher (P 0.001, P=0.002) for cattle treated with DRAXXIN than for those treated with Nuflor. In Study 1, first-treatment success for animals that received DRAXXIN was 73.7% compared with 30.3% for those that received Nuflor. In Study 2, first-treatment success for animals that received DRAXXIN was 82% compared with 64% for those that received Nuflor. Removals associated with BRD (chronics plus mortalities), in both studies, were lower for the group that received DRAXXIN than for the group that received Nuflor. In one study, the difference was significant (P 0.001). Introduction DRAXXIN contains the active ingredient tulathromycin, the first of a new subclass of macrolide, the triamilides, discovered and developed by Pfizer Animal Health for use in livestock. DRAXXIN is a highly effective, single-dose antimicrobial medication indicated for treatment of BRD, and control of respiratory disease in cattle at high risk of developing BRD, caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni (Haemophilus somnus). DRAXXIN is formulated to have excellent syringeability, even at low temperatures, and a convenient low-volume dose (1 ml/40 kg; 1.1 ml/100 lb). When administered according to the label dose of 2.5 mg tulathromycin/kg body weight (BW), tulathromycin is rapidly absorbed, distributes widely (large apparent volume of distribution) and provides concentrations in bovine lung for an extended period. 1 Clinical efficacy of DRAXXIN for treatment of BRD, as well as for control of respiratory disease in cattle at high risk of developing BRD, has been well documented in multiple feedlot and stocker studies. 2,3,4 Reported here are results of 2 studies that compared the efficacy of DRAXXIN with that of Nuflor for the treatment of undifferentiated BRD in cattle and their subsequent feedlot performance and carcass characteristics. 1
Study 1 Materials and Methods In the spring of 2003, crossbred feeder steers (315 to 581 lb, 143 to 264 kg) purchased from auction markets in Minnesota, North Dakota, and Kansas, were transported to the study site in Nebraska, and processed (Figure 1). Processing at arrival included administration of BOVI- SHIELD 4, DECTOMAX Injectable Solution, ULTRABAC 7, and Ralgro Implants. Animals were observed daily and those exhibiting clinical signs of BRD were examined further. Clinical attitude scores (CAS) were assigned as follows: 0 = normal, bright, alert, responsive; 1 = mild depression; 2 = moderate to marked depression (may be reluctant to stand); 3 = severe depression (unable to stand without assistance); 4 = moribund, unable to rise. Calves that had a CAS 1 and rectal temperature 104 o F were selected by the investigator and randomly assigned, during 2 consecutive days, to receive treatment with a single dose of DRAXXIN (2.5 mg tulathromycin/kg BW) SC (n=100) or Nuflor (40 mg florfenicol/kg BW) SC (n=100). Day 0 was the day of enrollment and first treatment for each calf. Nasopharyngeal samples for bacterial isolation and identification were obtained from 20% of animals, randomly selected from each group, prior to treatment. Body weights for individual animals were recorded on day 0 (the day treatment was administered), if the animal required additional treatment, when an animal was removed from the study, day 28, at re-implanting on day 139 or 140, and at harvest on day 316 or 317. From days 3 through 28, a CAS was recorded daily for each animal, and those fulfilling re-treatment criteria (CAS of 1 or 2 plus a rectal temperature 104 o F, or a CAS of 3 or 4) received their 1st re-treatment (LA-200, 20 mg oxytetracycline/kg BW). Animals fulfilling these re-treatment criteria a second time received a 2nd retreatment (Baytril, 11 mg enrofloxacin/kg BW). Re-treated animals were observed daily, but received no other treatment for 3 days following each re-treatment (with LA-200 or Baytril). From day 29 to close, animals that exhibited clinical signs of BRD (CAS of 1, 2, 3 or 4, regardless of rectal temperature) met re-treatment criteria. Animals that were re-treated 3 times during days 3 through 28 or 3 times between day 29 and close were classified as chronics and removed from the study. All remaining cattle were harvested on day 316 or 317, depending on the day of enrollment. The study was conducted and analyzed according to the experimental design contained in the study protocol, which included random allocation of animals to groups, response data to be analyzed and statistical methods to be used. Results for Study 1 First-treatment success 5 for cattle treated with DRAXXIN was significantly higher (P 0.001) than for cattle treated with Nuflor (days 3 through 28: DRAXXIN, 73.7%, Nuflor, 30.3%; days 29 through close: DRAXXIN, 53.2%, Nuflor, 23.2%; Table 1). Frequency distribution of 1st re-treatments during days 3 to 28 (Figure 2a) revealed daily numerical differences for animals in each treatment group. Cumulative distribution of 1st re-treatments during days 3 to 28 (Figure 2b) revealed marked differences among treatment groups when the day-to-day variability of the frequency distribution accumulated. Overall, fewer animals that received first treatment with DRAXXIN required re-treatment than did those animals that received first treatment with Nuflor. Removals due to BRD (chronics plus mortalities) were significantly lower (P 0.001) for cattle treated with DRAXXIN than for cattle treated with Nuflor (days 3 through 28: DRAXXIN, 5.1%, Nuflor, 26.3%; days 3 through close: DRAXXIN, 20.2%, Nuflor, 47.5%; Table 1). During days 3 through close, 24 more cattle treated with Nuflor (42) were classified as chronics 6 and removed from the study than those treated with DRAXXIN (18; Table 1). More cattle that were treated with Nuflor (5) died due to BRD than those treated with DRAXXIN (1; Table 1). Average daily gain, calculated with mortalities and chronics removed, from days 0 through 28 was significantly higher (P=0.0001) for cattle treated with DRAXXIN (3.46 lb/day) than for cattle treated with Nuflor (2.40 lb/day). There was no significant difference (P=0.3877) for ADG from day 0 through close for the surviving cattle that received DRAXXIN or Nuflor (Table 2). There were no significant differences (P>0.05) for final live body weights, hot carcass weights (Table 3) or individual carcass variables (kidney/ pelvic/heart fat, fat thickness, marbling score, ribeye area, carcass quality and yield grades recorded after an overnight chill). Nasopharyngeal samples from 21 animals and pulmonary samples from 2 animals yielded P multocida, M haemolytica and H somni species with 9, 13, and 2 isolates, respectively. Samples from some animals yielded more than 1 organism. No adverse product-related experiences were reported. Figure 1. Experimental Design of Treatment Study 1 (Nebraska); DRAXXIN or Nuflor 2
Table 1. First-treatment and Re-treatment Successes for Treatment Study 1; DRAXXIN or Nuflor,* n (%) Days 3-28 Days 3-Close** DRAXXIN Nuflor DRAXXIN Nuflor P Value P Value Success (n=100) (n=100) (n=100) (n=100) First Treatment 73 (73.7%) 0.001 30 (30.3%) 50 (53.2%) 0.001 23 (23.2%) 1st Re-treatment 13 NA 20 7 NA 11 2nd Re-treatment 8 NA 23 12 NA 11 3rd Re-treatment 0 NA 0 4 NA 4 4th Re-treatment 0 NA 0 2 NA 3 BRD Removals 5 (5.1%) 0.001 26 (26.3%) 19 (20.2%) 0.001 47 (47.5%) Chronics 5 NA 21 18 NA 42 BRD Mortalities 0 NA 5 1 NA 5 Non-BRD Removals 1 NA 1 6 NA 1 NA = not analyzed. * First Treatment = DRAXXIN or Nuflor 1st re-treatment = LA-200 (20 mg oxytetracycline/kg BW) 2nd re-treatment = Baytril (11 mg enrofloxacin/kg BW) 3rd re-treatment = standard feedlot treatment and animal removed from study 4th re-treatment = standard feedlot treatment and animal removed from study Chronic = received 3 re-treatments and removed from study Re-treatment Criteria Days 3-28 - CAS of 1 or 2 and a rectal temperature of 104 o F; or CAS of 3 or 4 Days >28 - CAS of 1 ** Close was either day 316 or day 317 depending on day of enrollment. BRD-associated mortalities and chronics. All percents calculated with number enrolled minus non-brd removals as denominator. Non-BRD removals included non-brd associated-mortalities. Figure 2a. Frequency Distribution of Animals that Received Their 1st Re-treatment by Day, from Day 3 through Day 28; Treatment Study 1 (Nebraska); DRAXXIN or Nuflor Figure 2b. Cumulative Distribution of Animals that Received Their 1st Re-treatment by Day, from Day 3 through Day 28; Treatment Study 1 (Nebraska); DRAXXIN or Nuflor or Animals that Remained in Treatment 3
Table 2. Body Weight and Average Daily Gain for Animals that Remained in Treatment Study 1 (Nebraska); DRAXXIN or Nuflor Initial Body Weight* (lb) Final Body Weight (lb) Average Daily Gain* (lb/day) Days DRAXXIN P Value Nuflor DRAXXIN Nuflor DRAXXIN P Value Nuflor 0-28 437.1 0.5306 441.8 534.1 509.0 3.46 0.0001 2.40 28-Re-implant ** 534.1 0.0074 509.0 878.2 850.4 3.07 0.7836 3.05 Re-implant-Close 878.2 0.0556 850.4 1417.2 1404.0 3.05 0.3772 3.13 0-Close 437.1 0.5446 441.8 1417.2 1404.0 3.09 0.3877 3.04 * Least-Squares Mean. Repeated measures mixed model least-squares mean estimates of body weight and average daily gain did not include values for animals removed before day 28, or for mortalities or chronics removed prior to the day of re-implant or the day of harvest. Note: Mortalities and chronics removed. ** Re-implant occurred on day 139 or day 140. Close was day 316 or day 317 depending on day of enrollment. Table 3. Carcass Adjusted Least-Squares Mean Final Body Weight, Weight Gain, Average Daily Gain and Hot Carcass Weight to Close* for Animals that Remained in Treatment Study 1 (Nebraska); DRAXXIN or Nuflor, n (SEM) DRAXXIN P Value Nuflor Number of Animals 75 52 Final Body Weight, lb 1378.0 (15.6) 0.8194 1372.4 (18.7) Weight Gain, lb 937.8 (14.15) 0.7161 929.7 (16.99) Average Daily Gain, lb/day 2.95 (0.04) 0.7161 2.93 (0.05) Hot Carcass Weight, lb 895.7 (10.1) 0.8194 892.1 (12.2) * Mortalities and chronics removed. Study 2 Materials and Methods Another study was performed in the spring of 2003 with feeder steers (348 to 692 lb, 158 to 314.5 kg) purchased from auction markets in Tennessee and transported to the study site in Colorado (Figure 3). Processing at arrival included administration of BOVI-SHIELD IBR/BVD, DECTOMAX, and Component E-S Implant. Calves that had a CAS 1 and rectal temperature 104 o F were selected by the investigator and randomly assigned, during 3 consecutive days, to receive treatment with a single dose of DRAXXIN (2.5 mg tulathromycin/kg BW) SC (n=100) or Nuflor (40 mg florfenicol/kg BW) SC (n=100). Animals from each treatment group (DRAXXIN or Nuflor) were commingled. Cattle with a CAS of 1 or 2 plus a rectal temperature 104 o F, or a CAS of 3 or 4, and that were at least 3 days post-treatment with DRAXXIN or Nuflor received their 1st re-treatment with A180 (6 mg danofloxacin/kg BW), followed approximately 48 hours later by a second dose (6 mg danofloxacin/kg BW). Animals received no other treatment between the 2 doses of A180. Animals fulfilling these re-treatment criteria a second time, and that were at least 2 days following the second dose of A180, received their 2nd re-treatment with LA-200 (20 mg oxytetracycline/kg BW). Animals that met these re-treatment criteria and were at least 2 days post-treatment with LA-200 were classified as chronics, and removed from the study. Re-treatment criteria and regimens were re-initiated on day 29. Animals that were re-treated 3 times during days 3 through 28 or 3 times between day 29 and close were classified as chronics and removed from the study. All animals remaining in the study were harvested on days 173 to 175. Results for Study 2 First-treatment success for cattle treated with DRAXXIN was significantly higher (P=0.002 for days 0 through 28, and P=0.009 for days 0 through close) than that for cattle treated with Nuflor (days 0 to 28: DRAXXIN, 82% and Nuflor, 64%; days 3 through close: DRAXXIN, 79.4% and Nuflor, 63.6%; Table 4). The frequency distribution of 1st re-treatments during days 3 to 28 (Figure 4a) revealed daily numerical differences for animals treated in each treatment group. Cumulative distribution of 1st re-treatments during days 3 to 28 (Figure 4b) revealed marked differences between treatment groups when the day-to-day variability of the frequency distribution accumulated. Overall, fewer animals that received first treatment with DRAXXIN required re-treatment than did those animals that received Nuflor. Removals due to BRD were not significantly different (P=0.058) for either treatment group during days 0 through 28, and for days 0 through close. The ADG was not significantly different for days 0 through 28 (P=0.7152), days 28 through day of re-implanting (P=0.7931), or days 0 through close (P=0.1113) for cattle in Figure 3. Experimental Design of Treatment Study 2 (Colorado); DRAXXIN or Nuflor 4
Table 4. Treatment and Re-treatment Successes*; Field Study 2 (Colorado): DRAXXIN or Nuflor, n (%) Days 3-28 Days 3-Close** DRAXXIN Nuflor DRAXXIN Nuflor P Value P Value Success (n=100) (n=100) (n=100) (n=100) First Treatment 82 (82%) 0.002 64 (64%) 77 (79.4%) 0.009 63 (63.6%) 1st Re-treatment 13 NA 23 12 NA 19 2nd Re-treatment 2 NA 4 3 NA 6 3rd Re-treatment 0 NA 0 1 NA 1 4th Re-treatment 0 NA 0 0 NA 0 BRD Removals 3 (3%) 0.058 9 (9%) 4 (4.1%) 0.058 10 (10.1%) Chronics 3 NA 9 3 NA 10 BRD Mortalities 0 NA 0 1 NA 0 Non-BRD Removals 0 NA 0 3 NA 1 NA = not analyzed. * First Treatment = DRAXXIN or Nuflor 1st re-treatment = A180 (2 doses, 6 mg danofloxacin/kg BW with approximately 48-hour interval) 2nd re-treatment = LA-200 (20 mg oxytetracycline/kg BW) 3rd re-treatment = standard feedlot treatment and animal removed from study 4th re-treatment = standard feedlot treatment and animal removed from study Chronic = received 3 re-treatments and removed from study Re-treatment Criteria Days 3-28 and days 29 to close - CAS of 1 or 2 and a rectal temperature of 104 o F; or CAS of 3 or 4 ** Close was day 173 to 175 (mean = 173). BRD-associated mortalities and chronics. All percents calculated with number enrolled minus non-brd removals as denominator. Non-BRD removals included non-brd associated-mortalities. Figure 4a. Frequency Distribution of Animals that Received Their 1st Re-treatment by Day, from Day 3 through Day 28; Treatment Study 2 (Colorado): DRAXXIN or Nuflor Figure 4b. Cumulative Distribution of Animals that Received Their 1st Re-treatment by Day, from Day 3 through Day 28; Treatment Study 2 (Colorado): DRAXXIN or Nuflor 5
Table 5. Body Weight and Average Daily Gain for Animals that Remained in Treatment Study 2 (Colorado); DRAXXIN or Nuflor Initial Body Weight* (lb) Final Body Weight (lb) Average Daily Gain* (lb/day) Days DRAXXIN P Value Nuflor DRAXXIN Nuflor DRAXXIN P Value Nuflor 0-28 534.7 0.0858 512.9 612.6 588.9 2.78 0.7152 2.72 28-Re-implant ** 612.6 0.0875 588.9 912.6 891.1 4.35 0.7931 4.38 Re-implant-Close 912.6 0.2427 891.1 1176.4 1178.4 3.47 0.0054 3.78 0-Close 534.7 0.9240 512.9 1176.4 1178.4 3.71 0.1113 3.85 * Least-Squares Mean. Repeated measures mixed model least-squares means estimate of body weight and average daily gain did not include values for animals removed before day 28, or for mortalities or chronics removed prior to the day of re-implant or the day of harvest. Note: Re-implant occurred on either day 97 or day 99 (mean=97). Close was on either day 173 or day 175 (mean=173). Table 6. Carcass Adjusted Least-Squares Mean Final Body Weight, Weight Gain, Average Daily Gain and Hot Carcass Weight to Close* for Animals that Remained in Treatment Study 2 (Colorado); DRAXXIN or Nuflor, n (SEM) DRAXXIN P Value Nuflor Number of Animals 93 88 Final Body Weight, lb 1112.6 (15.13) 0.7473 1106.1 (15.54) Weight Gain, lb 576.3 (10.60) 0.3290 591.2 (10.90) Average Daily Gain, lb/day 3.33 (0.06) 0.3290 3.42 (0.06) Hot Carcass Weight, lb 723.2 (9.83) 0.7473 718.9 (10.10) * Chronics and mortalities removed. either treatment group (Table 5). There were no significant differences (P>0.05) for final live body weights, hot carcass weights (Table 6) or individual carcass variables (kidney/pelvic/heart fat, fat thickness, marbling score, carcass quality and yield grades after an overnight chill). Ribeye area for cattle treated with DRAXXIN (13.98 in 2 ) was significantly larger (P=0.0396) than that for cattle treated with Nuflor (13.50 in 2 ). No adverse product-related experiences were reported. Discussion Bacteria isolated from clinically affected cattle prior to initial treatment during this study were consistent with those associated with BRD. 7,8 DRAXXIN is approved for treatment and control of BRD caused by M haemolytica, H somni and P multocida. DRAXXIN was more efficacious than was Nuflor, based on response to first treatment in both studies reported here. The substantial response to first treatment with DRAXXIN was followed by fewer re-treatments than for cattle that received Nuflor. That finding, in light of the different medications used for 1st and 2nd re-treatment, suggests that the choice of medication for first treatment had a major influence on response to subsequent treatment. Frequency distribution and cumulative distribution for 1st re-treatments should be considered when evaluating clinical response to treatment against BRD because they provide excellent, though different, views of the same information. The number of BRD-associated removals (mortalities and chronics) was significantly (P<0.05) different for the 2 treatment groups in Study 1. In Study 2, the difference of BRD-associated removals for the 2 treatment groups was not significant at P=0.05 but was at P=0.058. That latter P value indicates that there was a 94.2% probability that the difference in BRD removals found in Study 2 was actually attributable to DRAXXIN. 9 Re-treatment criteria were consistent within each phase of these studies, but were different in the first phase (days 3 through 28) from those in the second phase (days 29 through close). As a result, a few animals were re-treated more than 3 times, throughout the course of the study, before they were classified as chronics and removed from the study. In 1 of the 2 studies reported here, ADG for animals that remained in the studies was greater for those treated with DRAXXIN than for those treated with Nuflor. In order to minimize confounding influences on results, animals were randomly assigned to receive one of the respective medications being evaluated. Management practices and processing at each site of investigation were consistent for all animals within a given study. Recording of the disposition of animals removed from the studies (BRD-associated or non-brdassociated removals) was not included in the protocol; therefore, that information is not available for analysis or discussion. Before each study began, regimens for administration of those medications as well as subsequent medication (if needed) were stated in the respective protocols. Criteria for administration of subsequent medication and for classifying the responses were also defined to be consistent within the study. Because those steps were implemented, results within a given study could be attributed to the respective medication being evaluated. 6
Conclusions Results of these treatment studies provide evidence that DRAXXIN administered as a single SC injection was safe and significantly more effective than was Nuflor for the treatment of undifferentiated BRD in cattle used in these studies. In both studies, DRAXXIN resulted in greater first-treatment success and lower BRD-associated removals (mortalities and chronics). Do not use DRAXXIN in female dairy cattle 20 months of age or older. Effects on reproductive performance, pregnancy and lactation have not been determined. Do not use in calves to be processed for veal. Do not use in chickens or turkeys. Do not use in animals known to be hypersensitive to the product. References 1 Nowakowski MA, Inskeep P, Risk J, et al. Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle. Vet Ther 2004;5:60-74. 2 Nutsch RG, Skogerboe TL, Rooney KA, Weigel DJ, Gajewski K, Lechtenberg KF. Comparative efficacy of tulathromycin, tilmicosin and florfenicol in the treatment of bovine respiratory disease in stocker cattle. Vet Ther 2005; in press. 3 Skogerboe TL, Rooney KA, Nutsch RG, Weigel DJ, Gajewski K, Kilgore WR. Comparative efficacy of tulathromycin versus florfenicol and tilmicosin against undifferentiated bovine respiratory disease in feedlot cattle. Vet Ther 2005; in press. 4 Rooney KA, Nutsch RG, Skogerboe TL, Weigel DJ, Kimberly K, Kilgore WR. Comparative efficacy of tulathromycin for the control of respiratory disease in cattle at high risk of developing bovine respiratory disease. Vet Ther 2005: in press. 5 First-treatment success = did not meet criteria for subsequent treatment, referred to as retreatment. 6 Chronic = received 3 re-treatments and removed from study. 7 Mosier DA. Bacterial pneumonia, bovine respiratory disease update. Vet Clin North Am Food Anim Pract 1997;13(3):483-493. 8 Ames TR, Baker JC, Wikse SE. Lower respiratory tract diseases. In: BP Smith, ed. Large Animal Internal Medicine, 3rd ed. St. Louis, MO: Mosby, Inc; 2002; 550-570. 9 SAS. SAS/STAT Userʼs Guide. Version 8. Cary, NC: SAS Institute Inc; 1999. Prepared from study reports 2132T- 60-01-050 and 1133R-60-02-376. DRAXXIN, BOVI-SHIELD and the Beef Friendly logo are trademarks of Pfizer Inc. A180, DECTOMAX, LA-200 and ULTRABAC are registered trademarks of Pfizer Inc. Component is a registered trademark of Ivy Animal Health Inc. Nuflor and Ralgro are registered trademarks of Schering-Plough Animal Health. 2005 Pfizer Inc. All rights reserved. DRX05019 7
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